1. Field of the Invention
The invention relates to the prevention and/or termination of malignant sustained ventricular tachyarrhythmia. Ventricular tachyarrhythmia can be followed by ventricular fibrillation, which can lead to sudden death, and occurs primarily in patients having cardiomyopathies, such as myocardial ischemia, myocardial infarction, or other conditions which cause ischemia of cardiac tissue. The high incidence of recurrent ventricular fibrillation and sudden death in survivors of cardiac arrest underscores the need for an effective approach to prophylactic treatment in these patients.
2. Brief Description of the Art
Ventricular tachyarrhythmias arising from myocardial ischemia and infarction are a leading cause of sudden cardiac death (SCD) in the United States. Malignant ventricular tachyarrhythmias occur in patients with coronary artery disease commonly in association with acute coronary artery occlusion and a previously healed myocardial infarction (Gillum, 1989; Liberthson et al., 1974). Identifiable risk factors include but are not limited to: a) an underlying substrate capable of sustaining a reentrant ventricular arrhythmia (Kleiman et al., 1988; lesaka, 1990); b) an increased sympathetic nervous system tone (Kleiger et al., 1987); and c) reduced ventricular function and frequent ventricular ectopy (Bigger et al., 1984; Moss et al., 1979).
The importance of increased sympathetic tone (increased sympathetic nervous system activity, increased circulating catecholamines, and/or increased β-adrenergic receptor sensitivity) as a risk factor for sudden death is underscored by the efficacy of β-adrenergic receptor antagonists in reducing mortality during acute myocardial ischemia (Hjalmarsson et al., 1981) and during the recovery phase of myocardial infarction (β-Blocker Heart Attack Trial Research Group, 1982; Olsson et al., 1985). Although β-adrenergic receptor blockade is the accepted pharmacologic basis for their protective actions, the electrophysiologic bases for their protective actions are less well-defined.
Both increased sympathetic nervous system tone (Malliani et al., 1980) and increased βAR sensitivity (Cameron et al., 1982) have been documented during the first 24 hours in canine models of myocardial infarction. An altered responsiveness of the myocardium to adrenergic stimuli under conditions of ischemia is an important mediator of triggered beats and/or delayed reentry resulting in ventricular tachyarrhythmias and sudden cardiac death. Epicardial border zone (EBZ) tissue is recognized as the substrate for development of recurrent ventricular arrhythmias, including ventricular tachycardia and subsequent propagation to ventricular fibrillation and SCD (Steinberg et al., 1995; Yamada et al., 1992; Dangman et al., 1988). Triggered beats in the EBZ overlying the infarct after 24 hours have been studied in detail (Dangman et al., 1988). It has been demonstrated that abnormal electro-physiological activity is obtained upon exposure to a β-agonist indicating enhanced tissue sensitivity to β-agonists during the first 24 hours after ischemia.
Increased sympathetic nervous system activity augments ventricular arrhythmia development during the first 30 minutes following coronary artery occlusion. The facilitatory role of the sympathetic nervous system can be established by the increased incidence of ventricular arrhythmia and increased incidence of ventricular fibrillation observed during cardiac sympathetic nerve stimulation (Schwartz et al., 1981; Euler et al., 1985), and a decreased incidence and severity of ventricular arrhythmias observed following β-adrenergic receptor blockade (9,10) or transection of sympathetic nerves innervating the heart (Harris et al., 1951; Milch et al., 1955). An even more critical role for the sympathetic nervous system is suggested for experimental arrhythmia models wherein acute ischemia is interposed upon previous myocardial infarction. The presence of high sympathetic nervous system tone is crucial for the initiation of lethal ventricular arrhythmia in the dog when an acute ischemic episode is superimposed upon previous myocardial infarction (Schwartz et al., 1980; Patterson et al., 1982), and lethal arrhythmias were markedly suppressed with the administration of β-adrenergic receptor antagonists (Patterson et al., 1983; DeFerrari et al., 1993).
Although there is a clear association between increased sympathetic nervous system tone and an increased incidence of lethal ventricular arrhythmia during an acute episode of myocardial ischemia in animal models, the importance and mechanism(s) of increased sympathetic tone as a risk factor for lethal arrhythmia observed during subacute recovery phase from myocardial infarction is less well established.
Electrocardiographic recordings obtained from ambulatory patients at the time of sudden death demonstrate an increase in rapid ventricular ectopy preceding either sustained monomorphic, or less commonly, polymorphic tachycardia consistent with triggering of an underlying reentrant substrate by ventricular premature beats (Kempf et al., 1984; Panidis et al., 1983). In the experimental model of the present invention described herein below, a canine model of sudden arrhythmic death is utilized, occurring during a 2 to 24 hr period following two stage left anterior descending (LAD) coronary artery occlusion, which incorporates several of those features observed in man (Patterson et al., 1986; Patterson et al., 1991; Patterson et al., 1991).
Tissue TNFα increases in myocardial infarction (Gurevitch et al., 1996; Frangogiannis et al., 1998; Irwin et al., 1999; Torre-Amione et al., 1996). This serves as one of several cytokine-mediated attractants for neutrophil migration into the ischemic region and enhances the inflammatory reaction that is related to progressive tissue destruction (Entman et al., 1994; Youker et al., 1994). These mediators of inflammation result in loss of cellular function, widespread destruction, proteolysis and apoptosis in the infarct region. These events are also observed to a lesser and variable extent in adjacent regions such as the EBZ.
β-Adrenergic receptor kinase 1 (βARK), a member of the G-protein receptor kinase (GRK) superfamily, diminishes β-AR sensitivity by phosphorylation of the target receptors (Krupnick et al., 1998; Pitcher et al., 1998; Bunemann et al., 1999). Changes of the endogenous β-AR modulator also have been shown to modulate tissue-specific β-AR changes in sensitivity to agonist stimulation (Koch et al., 1995; Ungerer et al., 1996; Ping et al., 1997). A rapid decrease in βARK expression and activity in EBZ tissue following LAD ligation has been previously reported by the inventors (Yu et al., 2000). This was associated with a decreased ability of the affected cardiac tissue to desensitize to β-AR agonist-induced signal transduction during a period extending at least from 6 to 24 hours after coronary artery ligation in the dog. This EBZ tissue therefore becomes more vulnerable to β-AR-induced arrhythmias.
Therefore, there exists a need in the art for new and improved compositions for treating and/or preventing ventricular tachyarrhythmias, including sustained monomorphic ventricular tachyarrhythmias, in response to mycordial ischemia and/or infarction, as well as methods of using same, that overcome the disadvantages and defects of the prior art. It is to such compositions and methods of treatment, wherein the composition inhibits substantial loss of β-ARK activity and/or expression, that the present invention is directed.